Diabetic retinopathy is the leading cause of blindness in the working-age population of the United States, and nearly everyone with type-1diabetes and more than 60% with type-2 diabetes have some level of retinopathy after being diabetic for 20 years. The importance of understanding the progression of retinopathy cannot be overstated due to the lack of available treatments, which in part is a consequence of a deficiency in our knowledge of the pathological mechanisms. Many investigators suggest a central role for hypoxia in the progression of diabetic retinopathy, with several factors contributing to ischemia and capillary occlusion. The loss of perfusion is thought to lead to insufficient oxygen delivery and subsequent production of angiogenic factors, with consequential growth of permeable and hemorrhaging vessels on the surface of the retina that interferes with light transmission. Our primary hypothesis to be tested in the proposed work is novel and fills an important void in our understanding of diabetic retinopathy. We plan to explore the potential paradox that an early excess of oxygen leads to a subsequent deficiency of oxygen in the diabetic retina. Due to the central role in diabetic retinopathy that many researchers assign to hypoxia, it is not surprising that little attention has been given to the possible preceding role for excess oxygen. The initial hyperoxygenation that we hypothesize to occur in the diabetic retina could be related to the early decrease in oxygen consumption, which may be explained at least in part to the cell death and thinning of the retina. With this decrease in consumption, a normal flow of blood into the tissue would provide more oxygen than necessary to the remaining cells. An excess of oxygen induces autoregulatory vasoconstriction and a reduction in blood flow rate, which could contribute to capillary occlusion and ischemia that hampers neuronal function, nutrient delivery, and metabolite removal. Treatments designed to improve flow rates may exaggerate the existing oxygen excess, but unfortunately, increase the potentially harmful production of oxidants. Therefore, from a translational standpoint, it is necessary to consider both advantages and also disadvantages of vasodilatory interventions, as will be performed in the following specific aims: (1) Test the hypothesis that interventions directed toward enhancing retinal blood flow will exaggerate the hyperoxygenation that is present early in the diabetic retina, (2) Test the hypothesis that the exaggerated oxygen excess induced by vasodilatory interventions will enhance the production of oxidants in diabetic retinal tissue, (3) Test the hypothesis that vasodilatory interventions in the diabetic retina will be opposed by autoregulatory pathways of vasoconstriction that will attempt to limit hyperoxygenation, and (4) Test the hypothesis that vasodilatory interventions in the diabetic retina will attenuate capillary occlusion and improve neural function. PUBLIC HEALTH RELEVANCE: A large proportion of our population has diabetes, and most of these individuals will develop vision problems. Diabetic retinopathy is the leading cause of blindness in US adults, and patients with this disease have limited treatment options to prevent the decline in vision. The work proposed in this application targets the early phase of the disease, a time point in which we have discovered that too much retinal oxygen might cause harmful decreases in retinal blood perfusion.